We have demonstrated that the alpha l-adrenergic receptor acts directly on rat hepatocytes to enhance stimulated DNA synthesis (SCIENCE 227:749-51 (1985)), and that this receptor is also involved in the early stimulation of regenerative DNA synthesis in rat liver after 2/3 partial hepatectomy. At a crucial time in the prereplicative phase, the alpha 1 receptor is uncoupled from turnover of membrane phosphatidylinositol (its usual second messenger pathway), and it appears that this form of the receptor is responsible for growth-regulating activities. Additionally, in regenerating liver, this uncoupling is preceded by a fall in immunoreactive membrane p2l, the product of the ras family of cellular proto-oncogenes. The proposed project would examine the mechanism of stimulation by the alpha adrenergic receptor in rat hepatocellular growth, to understand the significance of receptor uncoupling, to seek other second messenger pathways used by these receptors, and to determine to what degree two models of hepatocyte proliferation (liver regeneration in vivo and alpha, stimulated DNA synthesis in primary culture) are comparable. These studies would also examine the role of p2l proteins in both models, and explore whether a link exists between one or more of them and the alpha 1 receptor. The ubiquitous nature of the alpha 1 receptor in tissues, the recent identification of similar receptors as oncogene products (e.g. angiotensin and serotonin receptors) and the still mysterious role of the ras proteins, genes for which are among the most commonly activated of oncogenes in human cancers, suggest that this will be a singularly valuable model to study.
